The present invention is extremely useful for the synthesis of novel neolignan frameworks in large quantities to have a scope for a wide range of biological activities including anticancer, anti-HIV, anti-inflammatory, antifungal, antioxidant and neuroleptic, which are reported for structurally similar neolignan frameworks. Lignans and neolignans are a large group of natural products characterized by the coupling of two C6-C3 units which are derived from cinnamic acid derivatives but present in small quantities in plants. The C6-C3 unit corresponding to a phenyl propane is numbered from 1 to 6 in benzene ring and α, β, γ in the propyl chain. For the second C6-C3 unit, the numbers are primed. If the linkage between two C6-C3 units, is through β-β′ then the compound is termed as lignan. If the linkage through any other positions, the compounds referred as neolighans (C. B. S. Rao, Chemistry of Lignans, Andhra University Press, Visakhapatanam, India, 1978, Ch-I, 1).
The aryl moieties of the lignans are substituted mostly with the hydroxyl (phenolic) or their corresponding methyl ethers and methylenedioxy function-alities (S. Jensen, J. Hansen and P. M. Boll, Phytochem., 1993, 33(3), 523). The oxidation of phenols could give rise to phenoxy radicals followed by coupling with a second phenoxyl radical forming lignans and neolignans (S. Fujisawa, T. Atsumi, Y. Murakami and Y. Kadoma, Arch. Immunol. Ther. Exp., 2005, 53, 28). The coupling can take place in three ways such as i) C—C(aryl-aryl): forming biphenyl type lignans, ii) C—C(aryl-propyl chain): forming phenyl propane cross coupling products, iii) C—O(aryl or propyl-phenoxy radicals): forming phenyl propane dimeric ethers. The third category of coupling products are named as oxy-neolignans. These oxy-neolignans are present both in chain and cyclic forms (G. P. Moss, Pure Appl. Chem., 2000, 72(8), 1493). The oxidation of phenols often yields phenoxy radicals which couple with little selectivity. The new C—C and C—O bonds are formed mainly in ortho- and para-positions to the phenolic hydroxyls (D. A. Whitig, Comprehensive Organic Synthesis, B. M. Trost, I. Fleming and G. Pattenden, Eds., Pergamon, Oxford, 1991, 3, 659). Synthetically useful reactions are obtained only when the reactive sites are blocked by substituents, for example from 2,6 and 2,4 substituted phenols, C—C bonded biphenyls can be obtained in good yields.
But the more interesting neolignans are derived from the propyl chain cross coupling products such as α-α′, α-β′, α-γ′, β-α′, β-γ′, γ-γ′, γ-α′, γ-β′. These skeletons are highly interesting and rare in nature. These frameworks are expected to exhibit highly significant and potent biological activities as the basic oxygenated aryl rings are retained with the formation of new C—C bonds in the propenyl chains. The propenyl chains can be activated by both ionic and radical mechanisms. Once the double bond is opened up the resulting ions/radicals will undergo cross coupling reactions to form new C—C bonds. The activation of double bonds can be achieved conventionally by thermal or photochemical means. Generally, activation of these double bonds are achieved in presence of acid catalysts such as mineral acids, lewis acids or organic acids. But these reactions are not only slow and low yielding but also non-regio and stereoselective.
The acidic montmorilonite clays found highly suitable for carbocationic reactions such as condensations, cycloadditions, rearrangements and redox reactions (P. Laszlo, Science, 1987, 235, 1473). Montmorillonite K10 catalyst reported to yield densely functionalized isomerized Baylies-Hillman products with a new C—C bond formation under solvent free conditions (P. Shanmugam and P. Rajasingh, Tetrahedron, 2004, 60, 9283). These clay catalysts have an added advantage as they are eco-friendly and play an important role in organic synthesis and manufacture of industrial products and serves as model reagents in Green Chemistry.
Microwave Organic Reaction Enhancement (MORE) Chemistry has been shown to affect several organic transformations such as cyclizations, alkyne functionalizations, condensations and rearrangements. These reactions were accelerated with very high yields under microwave irradiated conditions with and without solvent (S. Caddick, Tetrahedron, 1995, 51(38), 10403). The double bond activation of isoeugenol (allyl) to eugenol (cinnamyl) was affected under MORE conditions with almost quantitative yield (A. Loupy, A. Petit, J. Hamelin, F. T. Boullet, P. Jacquault and D. Mathe, Synthesis, 1998, 1213).
Although the plant derived products have found widespread applications in the field of pharmaceuticals, cosmetics, dyes and essential oils etc. as they are easily available, cheaper and safer than synthetic products, it is not always true. There are several phytochemicals which beyond a certain limit, diminishes the market potential of products such as phenyl propenes (E. C. miller, A. B. Swanson, D. H. Philips, T. L. Fletcher, A. Liem and J. A. Miller, Cancer research, 1983, 43(3), 1124; S. C. Kim, A. Liem, B. C. Stewart and J. A. Miller, Carcino-genesis, 1999, 20(7), 1303). The trans isomer (α-asarone) is found safer than the cis-(β-asarone) or allyl-(saffrole) isomers which are toxic and highly carcinogenic (J. B. Harborne and H. Baxter, Phytochemical Dictionary: A handbook of Bioactive compounds from plants, Taylor & Francis Ltd, Washington D.C., 1993, 474).
Some varieties of Acorus contain very high percentage of cis-phenyl propene (β-asarone, 70-90%) while some other contain very less (3-8%) (E. stahl and K. Keller, Planta Medica, 1981, 43, 128; G. Waltraud and O, Schimmer, Mutation research, 1983, 121, 191; G. Mazza, J. Chromatography, 1985, 328, 179; T. J. Motley, Economic Botany, 1994, 48, 397).
β-asarone is reported to be carcinogenic in animals and has been found to induce tumors in duodenal region after oral administration. It has also shown chromosome damaging effect on human lymphocytes in vitro after metabolic activation (J. M. Taylor, W. I. Jones, E. C. Hogan, M. A. Gross, D. A. David and E. L. Cook, Toxicol. Appl. Pharmacol, 1967, 10, 405; K. Keller, K. P. Odenthal and P. E. Leng, Planta Medica, 1985, 1, 6; G. Abel, Planta medica, 1987, 53(3), 251; M. Riaz, Q. Shadab, F. M. Chaudhary, Hamdard Medicus, 1995, 38(2), 50). As a result, the A. Calamus of Asia is Internationally banned for its use in pharmaceutical, perfumery and flavor industries.
Neolignans and lignans are known for their wide range of biological activities including anticancer, anti-HIV, hepatoprotective, antifungal, anti-bacterial, anti oxidant and plant growth regularity activities (J. Harmatha and L. Dinan, Phytochemistry, 2003, 2, 321).
Reference may be made to Mori et al. (K. Mori, M. Komatsu, M. Kido and K. Nakagawa, Tetrahedron, 1986, 42(2), 523) wherein peracetic acid has been used to oxidize the propenyl unit of anethole and a-asarone. The drawbacks are the products obtained mainly by coupling at β-β′ linkage forming diaryl terahydrofuran moieties with very low yields.
Reference may be made to Anjaneyulu et al. (A. S. R. Anjaneyulu and D. S. Kumar, Indian J. Chem., 1996, 35B, 1038) wherein phenolic oxidative coupling of phenyl propenoids was affected with phosphomolybdic acid impregnated silica gel. The drawbacks are the products formed by aryl-aryl dimerisation with no side chain cross coupling.
Reference may be made to Syrjanen et al. (K. Syrjanen and G. Brunow, Tetrahedron, 2001, 57, 365) wherein coniferyl alcohol and aposinol have been subjected to phenolic oxidation with Horseradish peroxidase. The drawbacks are the products formed mostly by the dimerisation reactions without affecting the cross coupling reactions.
Reference may be made to Cathala et al. (B. Cathala, V. A. Beghin and R. Douillard, C. R. Biologies, 2004, 327, 777) wherein coniferyl alcohol was subjected to coupling reactions in presence of peroxidase. The drawbacks are the products obtained by β-β and β-O-4 couplings.
Reference may be made to Sinha et al. (A. K. Sinha, R. Acharya and B. P. Joshi, J. Nat. Prod., 2002, 65(5), 764) wherein β-asarone is subjected to oxidation with DDQ. The drawbacks are the formation of tran-2,4,5-trimethoxy cinnamaldehyde by oxidation of the double bonded methyl with no traces of cross coupling products.
Reference may be made to Sinha et al. (A. K. Sinha, R. Acharya and B. P. Joshi, US Patent No: WO03082786, 2003) wherein β-asarone or α-asarone rich A. calamus is oxidized with DDQ with or without solid support of silica gel or alumina in dry organic solvent. The drawbacks are isomerisation and oxidation of the propenyl unit was observed instead of cross coupling product formation.
Reference may be made to Adams et al. (J. M. Adams, S. E. Davies, S. H. Graham and J. M. Thomas, J. Catalysis, 1982, 78, 197) wherein the dimerisation of anithole [1-(4-metoxybenzene)-prop-1-en] has been affected with di- and tri-valent cation exchanged montmorillonites. The drawbacks are non-regioselectivity with low yields.
Reference may be made to Malhotra et al. (S. Malhotra and S. K. Koul, Phytochemistry, 1990, 29, 2733) wherein the dimerisation of 2,4,5-trimethoxyphenyl propene was carried out by sunlight irradiation. The drawbacks are the product formed is doubly cross coupled at α-α′ and β-β′ with very low yield (7%) and longer reaction time (40 hr.).
Reference may be made to Sinha et al. (A. K. Sinha, B. P. Joshi, R. Acharya, US Patent Application No: 20040049085, 2004) wherein the dimerisation of 2,4,5-trimethoxyphenyl propene was carried out and the corresponding neolignan dimer with a saturated alkyl chain was obtained in 3 steps. The drawbacks are use of toxic reagents like palladium and DDQ, inert atmosphere and pressure reactors. Further this method is multistep, time consuming and low yielding.
On the contrary, the present invention has been achieved under complete Green Chemistry conditions using a novel combination of montmorillonite acid clay catalyst and microwave irradiation and discloses single pot regioselective dimerisation of 2,4,5-trimethoxyphenyl propene (inseparable mixture of α- and β-asarones obtained as the major metabolite of Acorus calamus plant) of the formula 1 & 2 to form a novel neolignan viz: 3(R)-ethyl-2(S)-methyl-3-(2″,4″,5″-trimethoxy-phenyl)-1-(2′,4′,5′-trimethoxyphenyl)propane.